Biologic and biochemical effects of mitoxantrone.

ABSTRACT

Mitoxantrone (1,4-dihydroxy-5,8-bis[(2-[(2-hydroxyethyl)-amino]-ethyl) amino]-9,10-anthracenedione dihydrochloride) is a representative of a new class of chemical compounds with antineoplastic activity. It was one of a number of polycyclic aromatic compounds tested at the American Cyanamid Laboratories and was the most effective and potent derivative synthesized. Mitoxantrone produced significant increases in life span and long-term survivors when tested against P388 and L1210 leukemias, B16 melanoma, and colon tumor 26 transplanted into mice. In comparative animal trials, it proved more effective than most of the other agents tested, including doxorubicin, cyclophosphamide, methotrexate, cytarabine, and 5-fluorouracil. It was also active against intravenously implanted L1210 leukemia, in contrast to doxorubicin, though this is considered to have a similar mode of action. Mitoxantrone also demonstrated moderate activity against sublines of the mouse leukemias, which were resistant to anthracyclines. Significant therapeutic synergism against P388 leukemia was observed when mitoxantrone was administered on the same day as methotrexate and cytarabine or in sequence with cyclophosphamide, cisplatin, or vincristine sulfate. Mitoxantrone is active intraperitoneally, intramuscularly, subcutaneously, and intravenously, but oral activity has not been demonstrated. Although dose schedule did not appear critical, treatment every 4 days X 3 appeared to be the most effective. The mechanism of action of mitoxantrone has not been fully elucidated, but it is known to inhibit DNA and RNA synthesis. In cell culture, mitoxantrone induces nuclear aberrations with chromosomal scattering and morphologic alterations similar to those induced by doxorubicin. Drug-induced cell kill was not phase specific. Experiments with a resistant human colon carcinoma cell line (WiDr) indicated that resistance may be due to alterations of the cell membrane with decreased uptake. Mitoxantrone has markedly less cardiotoxicity than doxorubicin, and this may be linked to the fact that the drug does not induce free radical formation but inhibits lipid peroxidation.